Australian public assessment report for Dolutegravir (as sodium)

Therapeutic Goods Administration

May 2014

Australian Public Assessment Report for Dolutegravir (as sodium)

Proprietary Product Name: Tivicay

Sponsor: ViiV Healthcare Pty Ltd

About the Therapeutic Goods Administration (TGA)

The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices.

The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.

The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.

The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.

To report a problem with a medicine or medical device, please see the information on the TGA website .

About AusPARs

An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission.

AusPARs are prepared and published by the TGA.

An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications.

An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time.

A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.

Copyright

Commonwealth of Australia 2014This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to .

Therapeutic Goods Administration

AusPAR Tivicay ViiV Healthcare Pty Ltd Pty Ltd PM-2012-04124-1-2Final 19 May 2014

Page 3 of 89

ContentsList of the most common abbreviations used in this AusPAR5I. Introduction to product submission9Submission details9Product background9Regulatory status10Product Information10II. Quality findings11Drug substance (active ingredient)11Drug product11Biopharmaceutics11Quality summary and conclusions12III. Nonclinical findings12Introduction12Pharmacology12Pharmacokinetics15Toxicology17Nonclinical summary and conclusions24IV. Clinical findings28Introduction28Pharmacokinetics28Pharmacodynamics33Efficacy34Safety35Clinical summary and conclusions: first round36List of questions37Second round evaluation in response to questions38Clinical summary and conclusions: second round55V. Pharmacovigilance findings56Risk management plan56VI. Overall conclusion and risk/benefit assessment63Quality63Nonclinical64Clinical64Risk management plan76Risk-benefit analysis76Outcome87Attachment 1.Product Information88Attachment 2. Extract from the Clinical Evaluation Report88

List of the most common abbreviations used in this AusPAR

Abbreviation

Meaning

3TC

lamivudine

ABC

abacavir

ADME

absorption, distribution, metabolism, and excretion

AE

adverse event

AIDS

acquired immunodeficiency syndrome

ALP

alkaline phosphatase

ALT

alanine aminotransferase

ART

antiretroviral therapy

ASA

Australian Specific Annex

AST

aspartate aminotransferase

ATV

atazanavir

AUC

area under the plasma concentration-time curve

AUC0-

area under the plasma concentration-time curve from time zero to time infinity

BCRP

Breast Cancer Resistance protein

BCV

boceprevir

BID

bis in die (twice daily)

BMCs

blood mononuclear cells

Cmax

maximum plasma drug concentration

C

pre dose (trough) concentration at the end of the dosing interval

CDC

Centres for Disease Control

CI

confidence interval

CL/F

apparent clearance

CMI

Consumer Medicines Information

CNS

central nervous system

CSR

Clinical Study Report

DILI

drug induced liver injury

DRV

darunavir

DTG

dolutegravir

Emax

maximum response achievable from a drug

ECG

electrocardiogram

EFV

efavirenz

EMA

European Medicines Agency

ET

etravirine

EVG

elvitegravir

FDA

Food and Drug Administration (US)

FPV

fosamprenavir

FTC

emtricitabine

GD

gestational day

GI

gastrointestinal

GLP

Good Laboratory Practice

HBV

hepatitis B virus

HCV

hepatitis C virus

HIV

human immunodeficiency virus

IC50

inhibitory concentration 50%

IC90

inhibitory concentration 90%

ICH

International Conference on Harmonisation

IM

intramuscular

IN

integrase

INI

integrase inhibitor

IV

intravenous

LC-MS

liquid chromatography-mass spectrometry

LOEL

lowest observed effect level

LPV

lopinavir

mITT-E

Modified Intent to Treat Exposed

MRHD

maximum recommended human dose

MS

mass spectrometry

MSDF

Missing, Switch or Discontinuation = Failure

NMR

nuclear magnetic resonance

NNRTI

non nucleoside reverse transcriptase inhibitor

NOAEL

no observed adverse effect level

NOEL

no observed effect level

NRTI

nucleoside reverse transcriptase inhibitor

OMP

omeprazole

PBMCs

peripheral blood mononuclear cells

PD

postnatal day

PI

Product Information

PO

per os (oral administration)

PP

Per Protocol

PRO

protease

PSUR

Periodic Safety Update Report

QD

quaque die (once daily)

RAL

raltegravir

RBT

rifabutin

RMP

Risk Management Plan

RPV

rilpivirine

RTI

reverse transcriptase inhibitor

RTV

ritonavir

SAE

serious adverse events

SC

subcutaneous

SOC

System Organ Class

t1/2

terminal half-life

Tmax

time to reach maximum plasma concentration following drug administration

TDF

tenofovir disoproxil fumarate

TLOVR

time to loss of virologic response

TTC

threshold of toxicological concern

TVR

telaprevir

UGT

UDP-glucuronosyltransferase

V/F

apparent volume of distribution

XRPD

X-ray powder diffraction

I. Introduction to product submissionSubmission details

Type of Submission

New Chemical Entity

Decision:

Approved

Date of Decision:

17 January 2014

Active ingredient:

Dolutegravir (as sodium)

Product Name:

Tivicay

Sponsors Name and Address:

ViiV Healthcare Pty Ltd

Level 4, 436 Johnston Street

Abbotsford VIC 3067

Dose form:

Film coated tablets

Strength:

50 mg

Container:

High density polyethylene (HDPE) bottle

Pack size:

30 tablets

Approved Therapeutic use:

Tivicay is indicated for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in adults and children over 12 years of age and weighing 40 kg or more.

Route of administration:

Oral

Dosage:

50 mg once daily (patients infected with HIV-1 without resistance to the integrase class) or 50 mg twice daily (patients infected with HIV-1 with resistance to the integrase class)

ARTG Number

205212

Product background

This AusPAR describes a submission by the sponsor, ViiV Healthcare Pty Ltd, to register a new chemical entity, dolutegravir (DTG), with the trade name Tivicay. DTG is a 2-metal binding integrase inhibitor (INI) developed as a treatment for HIV-1 infection. DTG is a potent, low nanomolar inhibitor of both HIV integrase recombinant enzyme and of HIV replication in cell culture assays, retaining activity against major integrase resistance mutations. The proposed indication is:

For the treatment of human immunodeficienc